The invention relates generally to the field of chemistry, and in particular to the measurement of yields of reaction products. In one specific aspect, the invention relates to the use of mass spectroscopy to assist in determining the yields of reaction products. The invention also relates to techniques that may be used to potentially increase the yields of reactions.
An important pursuit of modern chemistry is the production of a wide variety of chemical products that may be used in numerous applications, such as, for example, pharmaceuticals, cleaners, paints, and the like. To produce such chemicals, one or more chemicals are reacted to produce one or more reaction products.
Many techniques for producing chemical products utilize solid supports having one or more linking sites where chemistries are performed. Further, one or more combinatorial processes may be employed as various chemical building blocks are reacted in a reaction sequence. Such techniques are efficient at producing relatively large chemical libraries. However, with these large libraries, relatively small amounts of each reaction products is produced, making it difficult to efficiently determine the yield of those reaction products. Even so, when producing reaction products, the resulting yield is of immense importance to chemists. Identification of the reaction conditions giving the highest yield of the desired product is both desirable and of commercial significance.
Hence, the invention relates to techniques for measuring the yield of reaction products in an efficient and a high throughput manner. Also, the invention relates to techniques for potentially increasing the yield of reaction products.
In one aspect of the invention, a method is provided for calculating the yield of a reaction product. The method utilizes a solid support with a first link, a reference material, and a second link having an attachment site. Chemistry is performed on the attachment site of the second link in one or more steps to produce a reaction product. The amount of the reference material and the reaction product are measured, and the percentage yield of the reaction product is determined based at least in part on the amount of measured reference material and the amount of measured reaction product. For example, the measuring step may comprise counting the number of ions of the reference material and the reaction product, and the yield may be determined by dividing the number of counted ions of the reaction product by the number of counted ions of the reference material.
In one aspect, the chemistry performing step comprises reacting the attachment site with a chemical building block to produce the reaction product. Alternatively, the chemistry performing steps may comprise reacting the attachment site with a first chemical building block to produce an intermediate product, and reacting the intermediate product with a second chemical building block to produce the reaction product. In still another alternative, the chemistry performing steps may comprise reacting the attachment site with a first chemical building block to produce an intermediate product, and carrying out a chemical transformation of the intermediate reaction product to produce the reaction product.
In another embodiment, a method for calculating the yields of reaction products using a mass spectrometer comprises counting the number of ions of the reference component and the corresponding reaction products that have been cleaved from multiple solid supports. The efficiency with which the reference materials and the products are detected by a given mass spectrometer is then determined. The percentage yield of each reaction product is calculated based at least in part on the amount of the number of counted ions of the associated reference material, the counted number of ions for the reaction product, and the determined efficiency.
Conveniently, the efficiency with which the mass spectrometer may detect the reference materials and the reaction products may be determined by producing multiple equations where each equation sets the ion counts of each reference material equal to the sum of a coefficient multiplied by the ion counts of the associated reaction product. After solving for the coefficients of the equations, the yields may be calculated by multiplying the coefficients by the number of ion counts of each product and dividing the product by the number of ion counts of the associated reference material.
In yet another embodiment, a method is provided for evaluating the yields of multiple chemical reactions where different reaction conditions are used in an attempt to increase the yield of a given reaction sequence. According to the method, multiple solid supports are provided which each include a first link, a reference material, and a second link having an attachment site. Chemistry is performed on the attachment sites of the second links in one or more steps and under different reaction conditions to produce a reaction product for each solid support. The percentage yield of the reaction products are determined based at least in part the amount of measured reference material. The yields may then be associated with the reaction conditions to determine which reaction conditions provided the best yields. Further, any side products may also be evaluated to determine if the process may be useful in developing a given reaction product.
Conveniently, the solid supports may further include a reaction condition code (which may also serve as the reference material) that is indicative of the reaction conditions used when performing the chemistries. This code may then be decoded to determine the reaction conditions. The use of such a code is particularly useful when the reactions are performed using mix and split techniques as is known in the art. Exemplary reaction conditions which may be employed include time, temperature, solvents, reagents, pressure, catalysts, and the like.
The invention also provides an exemplary chemical construct which comprises a solid support and a linking component having an attachment site. A ligand component is linked to the attachment site. The construct also includes a coding component which includes coded information on at least one reaction condition utilized when producing the ligand component. In this way, the reaction condition may be determined by simply evaluating the coding component. Preferably, the coding component comprises a mass code which is readable using a mass spectrometer. Once the mass of the code is measured, a look-up table is searched to identify the reaction condition.